Memantine in
moderate-to-severe Alzheimer's disease.
Reisberg B, Doody R,
Stoffler A,
Schmitt F, Ferris S, Mobius HJ
Memantine Study Group.
Department of Psychiatry,
New York University School of Medicine,
New York 10016, USA. barry.reisberg@med.nyu.edu
N Engl J Med 2003 Apr 3;348(14):1333-41
Abstract
BACKGROUND: Overstimulation of the
N-methyl-D-aspartate (NMDA) receptor by glutamate is implicated in
neurodegenerative disorders. Accordingly, we investigated memantine, an
NMDA antagonist, for the treatment of Alzheimer's disease.
METHODS: Patients with moderate-to-severe Alzheimer's disease were
randomly assigned to receive placebo or 20 mg of memantine daily for 28
weeks. The primary efficacy variables were the Clinician's
Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus)
and the Alzheimer's Disease Cooperative Study Activities of Daily Living
Inventory modified for severe dementia (ADCS-ADLsev). The secondary
efficacy end points included the Severe Impairment Battery and other
measures of cognition, function, and behavior. Treatment differences
between base line and the end point were assessed. Missing observations
were imputed by using the most recent previous observation (the last
observation carried forward). The results were also analyzed with only
the observed values included, without replacing the missing values
(observed-cases analysis).
RESULTS: Two hundred fifty-two patients (67 percent women; mean age, 76
years) from 32 U.S. centers were enrolled. Of these, 181 (72 percent)
completed the study and were evaluated at week 28. Seventy-one patients
discontinued treatment prematurely (42 taking placebo and 29 taking
memantine). Patients receiving memantine had a better outcome than those
receiving placebo, according to the results of the CIBIC-Plus (P=0.06
with the last observation carried forward, P=0.03 for observed cases),
the ADCS-ADLsev (P=0.02 with the last observation carried forward,
P=0.003 for observed cases), and the Severe Impairment Battery
(P<0.001 with the last observation carried forward, P=0.002 for
observed cases). Memantine was not associated with a significant
frequency of adverse events.
CONCLUSIONS: Antiglutamatergic treatment reduced clinical deterioration
in moderate-to-severe Alzheimer's disease, a phase associated with
distress for patients and burden on caregivers, for which other
treatments are not available.
